1. Field of the Invention
This invention relates to a novel and improved method of medical management for men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), involving combination therapy of administering therapeutically effective amounts of an .alpha..sub.1 -adrenergic antagonist, i.e., terazosin in combination with a phytotherapeutic agent, Serenoa repens (saw palmetto) extract.
2. Description of the Prior Art
Benign prostatic hyperplasia (BPH) is a common health related condition that affects many men as they age. Histologic changes that typify BPH are present in 50% of men by age 60 and approximately 90% by age 85 (Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age. J Urol. 1984; 132:474-479). BPH has a major impact on quality of life and exacts a heavy toll upon healthcare resources, including physicians, hospitals, and surgical facilities. In the United States, treatment of BPH exceeds $2 billion in costs, accounts for 1.7 million physician office visits, (Guess H A. Benign prostatic hyperplasia antecedents and natural history. Epidemiol Rev. 1992; 14:131-153) and results in more than 300,000 prostatectomies annually (McConnell J D, Barry M J, Bruskewitz R C. Benign Prostatic Hyperplasia. Rockville, Md.: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Services; 1994. Clinical Practice Guideline No. 8, AHCPR publication 94-0582).
Benign prostatic hyperplasia is a heterogeneous disorder shown in studies to be caused by hormonal factors, growth factors, stromal-epithelial interactions, and aging. It is a progressive condition, which results in increased frequency of urination, nocturia, a weak urine stream, hesitancy or delay in starting the urine flow and incomplete bladder emptying. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder, an increased incidence of urinary tract infection, urinary stone formation and renal failure.
Anatomically, the prostate is a fibromuscular and glandular organ that encircles the urethra at the bladder neck. It is situated in the true pelvis below the pubic bone and in front of the rectum. Its upper end (base) is continuous with the neck of the bladder, and its lower end (apex) rests on the pelvic floor. The urethra runs through the prostate from base to apex. The normal prostate is approximately 20 cc in size (volume) and measures between 3 and 4 cm at its widest portion; it is 4-6 cm in length and 2-3 cm in thickness. Structurally it is composed of fibromuscular tissue (30-50%) and glandular epithelial cells (50-70%). The fibromuscular component is present mostly anteriorly, while the glandular element is mostly in the posterior and lateral aspects of the organ. Anteriorly and laterally, a capsule composed of fibrous and smooth muscle tissue surrounds the prostate.
It is widely accepted that obstruction secondary to BPH occurs as a result of two factors: A dynamic component resulting from contraction of smooth muscle of the prostate and prostatic urethra mediated primarily by .alpha.-adrenergic receptors; and a mechanical component related to the presence of a mass of hyperplastic acinar or stromal tissue, which compresses and narrows the urethral lumen (Caine M: Alpha-adrenergic blockers for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1990; 17:641).
The ratio of epithelium to smooth muscle in the prostate can vary substantially among individual men, from 1:3 to 4:1. In general, however, larger prostates contain more androgen-dependent epithelial elements than smaller glands, which contain a higher proportion of smooth muscle. In either case, the outcome of BPH may be urethral obstruction, induced dynamically by smooth muscle contraction and mechanically by epithelial overgrowth, or by a combination of both.
After ruling out alternative causes of voiding disturbances, clinicians rely on surrogate markers to determine the presence of BPH. These include subjective assessments of lower urinary tract symptoms (LUTS) and objective measurements of flow rate and prostate volume. In 1993, the American Urological Association (AUA) developed a questionnaire to quantitate the severity of symptoms in patients with BPH (Barry M F, Fowler F J, O'Leary M P, et al, and the Measurement Committee of the American Urologic Association symptom index for benign prostatic hyperplasia. J Urol. 1992; 148:1549-1557). The AUA Symptom Index (AUASI) consists of seven questions related to the severity of urinary frequency, nocturia, weak urinary stream hesitancy intermittency, incomplete emptying, and urgency, each of which has a score of (0 to 5) . The maximum score is therefore 35. Patients with scores of (0 to 7) are good candidates for watchful waiting with periodic reevaluation. Men with moderate (8 to 19) to severe (20 to 35) scores usually require therapy to avoid complications.
A number of methodologies can be employed to estimate prostate volume, including magnetic resonance imaging (MRI), transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate specific antigen (PSA) level. DRE and PSA are by far the most practical and cost effective means of estimating prostate volume. PSA is a glycoprotein that is secreted in the cytoplasm of prostatic cells. Its function is to aid in the liquefaction of semen. Serum PSA is a useful proxy for prostate volume, according to a direct comparison of serum PSA levels and prostate volumes measured using TRUS or MRI. A strong log-log linear relationship was found between the two, although the slope of the relationship changes with advancing age. In light of these results, serum PSA may be used as a surrogate for prostate volume to identify patients with prostate enlargement over certain threshold sizes.
Epidemiological studies show that men with prostate volumes greater than 30 cc have a three fold higher risk of acute urinary retention (Jacobsen S J, Jacobson D J, Girman C J, Roberts R O, Rhodes T. Guess H A, Lieber M M. Natural History of Prostatism: Risk Factors for Acute Urinary Retention, J Urol. 1997; 158:481-487). Similarly, a recent clinical trial demonstrated that men with serum PSA levels greater than 1.4 ng/ml and 3.3 ng/ml were 2.0 and 4.2 times more likely to develop acute urinary retention respectively, than men with Serum PSA levels less than 1.4 ng/ml (McConnell J D, Bruskewitz R, Walsh P, et al for the PROSCAR Long-Term Efficacy and Safety Study (PLESS) Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998; 338(9): 557-563).
Estimations of prostate volume, either by DRE or serum PSA level, may be used to appropriately guide the selection of therapeutic alternatives, particularly when a goal of therapy is reduction of the risk for disease progression, development of urinary retention, and the need for BPH related surgery.
Treatment options for BPH include lifestyle modification, device, surgery, pharmacologic, and phytotherapeutic interventions. There are two classes of pharmacologic intervention: .alpha.-antagonists, which act via adrenergic pathways, and 5.alpha.-reductase inhibitors, which act via hormonal mechanisms. Alpha-Antagonists can be effective in relieving symptoms of BPH, whereas the 5.alpha.-reductase inhibitors have been shown to reduce prostate volume. Serenoa repens (saw palmetto) extract, a popular phytotherapeutic agent, has been shown to reduce prostate volume and to a lesser extent relieve symptoms and improve urine flow.
The therapeutic rationale for .alpha.-adrenergic blockade is two fold. A very large percentage of the hyperplastic prostate gland, at least 40% is comprised of smooth muscle, and that smooth muscle has a very high density of .alpha.-adrenergic receptors (Lepor H. .alpha..sub.1 -adrenoceptor selectivity: clinical or theoretical benefit? Br J Urol. 1995; 76 9 suppl. 1): 57-61). The sympathetic nervous system mediates the tension of prostatic muscle tissue via adrenergic receptors, specifically, the .alpha..sub.1 -adrenoceptors. Therefore, adrenoceptor stimulation is thought to be capable of increasing smooth muscle tone in the prostate, thereby placing constrictive pressure on the prostatic urethra and bladder neck, which induces obstructive symptoms (Beduschi M C, Beduschi R, Osterling J E. Alpha-blockade therapy for benign prostatic hyperplasia: from a nonselective to a more selective .alpha..sub.1A -adrenergic antagonist. Urology. 1998; 51:861-872). The mechanism of action of .alpha..sub.1 -antagonists presumably is to relax prostatic smooth muscle and, thus, relieve the obstructive symptoms characteristic of moderate to severe BPH.
Three synthetic pharmocologic .alpha..sub.1 -adrenergic antagonists have been approved by the FDA for the treatment of the symptoms of BPH e.g. terazosin (Hytrin.RTM.), doxazosin (Cardura.RTM.), and tamsulosin (Flomax.RTM.). These 3 agents provide prompt relief of symptoms, but do not alter prostate size.
The role of androgens in the development of benign prostatic hyperplasia in men is well documented (Wilson, N. Engl. J. Med. 317: 628-629, 1987). The enlargement of the prostate gland is dependent on the potent androgen, 5.alpha.-dihydrotestosterone (DHT). Luteinizing hormone-releasing hormone stimulates the pituitary gland to release luteinizing hormone, which stimulates the testes to produce testosterone (95% of which is produced by the testes). In the prostate cell, testosterone is converted to its more active metabolite 5.alpha.-dihydrotestosterone (DHT), by the enzyme Type II 5.alpha.-reductase. Then (DHT) binds to the cytoplasmic androgen receptor and the complex enters the cell's nucleus where it activates transcription of androgen-dependent genes.
Finasteride (sold under the trademark Proscar.RTM.) is a competitive and specific inhibitor of Type II 5.alpha.-reductase with which it slowly forms a stable enzyme complex. Finasteride has no affinity for the androgen receptor. Lowering of DHT leads to shrinkage of the enlarged prostate gland in most men (17.9% reduction of total prostate volume) compared to subjects receiving placebo. This can lead to gradual improvement of symptoms and urine flow over the next several months. Finasteride has also been shown to reduce the risk of acute urinary retention and the need for BPH-related surgery by 57% and 55%, respectively (McConnell J D, Bruskewitz R, Walsh P, et al for the PROSCAR Long-Term Efficacy and Safety Study (PLESS) Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998; 338(9): 557-563).
The usefulness of finasteride has been somewhat limited due to a multitude of undesirable side effects including impotence, decreased libido, ejaculatory disorders, and breast enlargement and tenderness (Agency for Health Care Policy and Research (AHCPR), "Treating Your Enlarged Prostate," AHCPR Publication No. 940584, 1994). Furthermore, finasteride causes a decrease in serum prostate specific antigen (PSA) levels by approximately 50% in patients with BPH, even in the presence of prostate cancer. This lowering of serum PSA levels may obscure its utility as a tumor marker for prostate cancer (Facts and Comparisons, Finasteride monograph, St. Louis, Mo.: Facts and Comparisons, Inc. 1999).
The use of phytotherapeutic agents, also known as plants or plant extracts, for the treatment of symptomatic BPH has been growing steadily throughout the world. In some European countries, plant extracts are the most commonly recommended initial treatment for men with obstructive voiding symptoms secondary to BPH. Serenoa repens (saw palmetto) is the most extensively studied phytotherapeutic agent used to treat lower urinary tract symptoms (LUTS) and BPH.
Saw palmetto extracts are derived from the dried ripe fruit of the American dwarf palm tree, Serenoa repens (also known by its botanical name Sabal serrulata) which is indigenous to the southeastern United States. The liposterolic extract of the Serenoa repens berry is comprised of a complex mixture of phytosterols and fatty acids. The mechanism of action of Serenoa repens is not known but may include alteration of cholesterol metabolism (Christensen M M, Bruskewitz R C. Clinical manifestations of benign prostatic hyperplasia and the indications for therapeutic intervention. Urol. Clin. North Am. 1990; 17:509-516), antiestrogenic, antiandrogenic, and anti-inflammatory effects (Marwick C. Growing use of medicinal botanicals forces assessment by drug regulators. JAMA. 1995; 273:607-609), and a decrease in available sex hormone-binding globulin (DiSilverio F. D'Eramo G, Lubrano C, et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostate tissue of benign prostatic hypertrophy patients. Eur Urol. 1992; 21:309-314). Animal studies have shown that liposterolic extracts of Serenoa repens inhibit competitively the binding to the cytosolic androgen receptor in prostate cells (Carilla E, et al. Binding of Permixon, A New Treatment For Prostatic Benign Hyperplasia, To The Cytosolic Androgen Receptor In The Rat Prostate. J Steroid Biochem, 1984; 20.1:521-523). These findings suggest that the beneficial effects observed in human trials may be a result of a direct action at the cytosolic androgen receptor.
A systematic review and quantitative meta-analysis of 18 randomized controlled trials involving 2939 men concluded that extracts from the saw palmetto plant, Serenoa repens improves urinary tract symptoms and flow measures in men with BPH. Furthermore, compared with finasteride, Serenoa repens produces similar improvements in urinary tract symptoms and flow measures, has fewer adverse treatment effects, and costs less (Wilt T J, et al. Saw Palmetto Extracts for Treatment of Benign Prostatic Hyperplasia. JAMA. 1998; 280:1604-1609.
A recent randomized double blind clinical trial examining the safety, efficacy, and mechanism of action of saw palmetto extract in men with symptomatic BPH demonstrated significant prostate epithelial atrophy (41% reduction of Transition Zone) compared to subjects receiving placebo. There were no significant adverse side effects or alterations in serum hormone or prostate specific antigen (PSA) levels (Marks L S. Clinical Effects of Saw Palmetto Extract in Men with Symptomatic BPH. American Urological Association 94.sup.th Annual Meeting. Dallas, Tex. May 4, 1999).
The primary benefits of treatment of BPH are: (1) improvement of symptoms, and (2) avoiding the harms of untreated disease. The two primary criterions for determining therapy for men with uncomplicated BPH are the American Urological Association (AUA) Symptom Score and prostate volume. Until recently, the risks of untreated BPH were difficult to define. However, epidemiologic data now demonstrates a clear correlation between prostate size and risks. These findings should have a significant impact on the long-term management of BPH.
It has become increasingly clear that matching each patient with the correct therapeutic agent or combination of agents can maximize the effectiveness of medical management of lower urinary tract symptoms and BPH. The evidence now suggests that patients with moderate to severe symptoms and smaller prostates (estimated volume less than or equal to 30 cc or serum PSA less than or equal to 1.4 ng/ml) are more likely to benefit from monotherapy with .alpha..sub.1 -adrenergic antagonists, while those with comparable symptoms and larger prostates (estimated volume &gt;30 cc or serum PSA &gt;1.4 ng/ml) may derive more durable results from combination therapy with an .alpha..sub.1 -adrenergic antagonist which acts upon the smooth muscle of the prostate alleviating the dynamic component of obstruction and an agent which reduces prostate size thereby addressing the mechanical component of obstruction.
U.S. Pat. No. 5,753,641 discloses a method of treatment for BPH involving combination therapy of a 5.alpha.-reductase inhibitor, finasteride (Proscar.RTM.), and an .alpha..sub.1 -adrenergic antagonist, i.e., terazosin.
The efficacy of combination therapy was recently validated in a 1-year study of combination therapy with terazosin and finasteride in men with "large prostates" (mean volume 46.8 cc) which demonstrated favorable results (Savage S, Spungen A, Galea G, Britanico J, Vapnek J. Combination medical therapy for symptomatic BPH. Can J Urol. In press, 1998). The symptom scores improved by almost an additional 2 units over those of the terazosin-alone arm; this difference was statistically significant (P&lt;0.05).
Despite these findings, combination therapy including finasteride is infrequently used in the medical management of BPH. This reality is primarily due to the troublesome adverse effects related to finasteride i.e. impotence, decreased libido, ejaculatory disorders, and breast enlargement and tenderness. Furthermore, serum PSA levels are lowered by 50% thereby obscuring its utility as a tumor marker for prostate cancer.
The above-mentioned U.S. Pat. No. 5,753,641 is disadvantageous since the 5.alpha.-reductase inhibitor component, finasteride (Proscar.RTM.), has an unfavorable adverse effect profile.
What would be particularly desirable in the art is a combination therapy both to treat the dynamic and mechanical obstructive effects of the BPH, while avoiding the adverse effects associated with the 5.alpha.-reductase inhibitor, finasteride (Proscar.RTM.).